The present invention is directed to Furo[3,2-c]Pyridine and Thieno[3,2-c]Pyridine compounds, their salts, compositions, and therapeutic uses, in particular, compounds that inhibit the activity of tyrosine kinase enzymes in animals, including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
RON (recepteur d'origine nantais) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. It is activated by binding to its natural ligand MSP and signals via the PI3K and MAPK pathways. RON can be deregulated in cancer by mechanisms such as over-expression of the receptor and/or the presence of constitutively active splice variants. Inhibition of RON has been shown to lead to a decrease in proliferation, induction of apoptosis and affects cell metastasis. RON overexpression is observed in a variety of human cancers and exhibit increased expression with progression of the disease.
MET is a receptor tyrosine kinase that is a heterodimeric protein comprising of a 50 kDa α-subunit and a 145 kDa β-subunit (Maggiora et al, J. Cell Physiol., 173:183-186, 1997). It is activated by binding to its natural ligand HGF (hepatocyte growth factor, also known as scatter factor) and signals via the PI3K and MAPK pathways. MET can be deregulated in cancer by mechanisms such as autocrine/paracrine HGF activation, over-expression of the receptor, and/or the presence of activating mutations. Significant expression of MET has been observed in a variety of human tumors, such as colon, lung, prostate (including bone metastases), gastric, renal, HCC, ovarian, breast, ESCC, and melanoma (Maulik et al, Cytokine & Growth Factor Reviews 13:41-59, 2002). MET is also implicated in atherosclerosis and lung fibrosis. Inhibition of MET can cause a decrease in cell motility, proliferation and metastasis, as reviewed in, e.g., Chemical & Engineering News 2007, 85 (34), 15-23.
As human cancers progress to a more invasive, metastatic state, multiple signaling programs regulating cell survival and migration programs are observed depending on cell and tissue contexts (Gupta and Massague, 2006). Recent data highlight the transdifferentiation of epithelial cancer cells to a more mesenchymal-like state, a process resembling epithelial-mesenchymal transition (EMT); (Oft et al., 1996; Perl et al., 1998), to facilitate cell invasion and metastasis (Brabletz et al., 2005; Christofori, 2006). Through EMT-like transitions mesenchymal-like tumor cells are thought to gain migratory capacity at the expense of proliferative potential. A mesenchymal-epithelial transition (MET) has been postulated to regenerate a more proliferative state and allow macrometastases resembling the primary tumor to form at distant sites (Thiery, 2002). MET and RON kinases have been shown to play a role in the EMT process (Camp et al., 2007; Grotegut et al., 2006; Wang et al., 2004).
Thus, it is desirable to identify compounds that inhibit RON and/or its related family MET for use in proliferative diseases, such as, but not limited to, cancer.
It has been documented in vitro that RON and MET can form heterodimers and signal via such RON-MET dimers. Since co-expression of RON and MET in cancer has been observed, such “cross-talk” may contribute to tumor growth. It is therefore especially desirable to identify compounds that inhibit both RON and MET.
There is a continuing need to improve anticancer pharmaceuticals with better selectivity or potency, reduced toxicity, or fewer side effects.